Improved diagnosis of inflammatory bowel disease and prediction and monitoring of response to anti-TNF alpha treatment based on measurement of signal transduction pathway activity

Abstract

Objective: Ulcerative colitis (UC) and Crohn’s disease (CD) are two subtypes of chronic inflammatory bowel disease (IBD). Differential diagnosis remains a challenge. Anti-TNFα treatment is an important treatment for IBD, yet resistance frequently occurs and cannot be predicted. Consequently, many patients receive ineffective therapy with potentially adverse effects. Novel assays are needed to improve diagnosis, and predict and monitor response to anti-TNF-α compounds.Design: Signal transduction pathway (STP) technology was used to quantify activity of STPs (androgen and estrogen receptor, PI3K, MAPK, TGFβ, Notch, Hedgehog, Wnt, NFκB, JAK-STAT1/2, and JAK-STAT3 pathways) in colon mucosa samples of CD and UC patients, based on transcriptome analysis. Previously described STP assay technology is based on computational inference of STP activity from mRNA levels of target genes of the STP transcription factor.Results: Results show that NFκB, JAK-STAT3, Wnt, MAPK, and androgen receptor pathways were abnormally active in CD and UC. Colon and ileum-localized CD differed with respect to STP activity, the JAK-STAT1/2 pathway being abnormally active in ileal CD. High activity of NFκB, JAK-STAT3, and TGFβ pathways was associated with resistance to anti-TNFα treatment in UC and colon-located CD, but not in ileal CD. Abnormal STP activity decreased with successful treatment.Conclusion: We believe that measuring mucosal STP activity provides clinically relevant information to improve differential diagnosis of IBD and prediction of resistance to anti-TNFα treatment in patients with colon-localized IBD, and provides new targets for treatment and overcoming anti-TNFα resistance.

Predictive, preventive and personalised approach as a conceptual and technological innovation in primary and secondary care of inflammatory bowel disease benefiting affected individuals and populations

“…Very recently, it was found that the proportion of plasma cells at baseline could predict anti-TNF therapy response in two independent cohorts with an accuracy of 82% [27], and non-responders for either IFX or VDZ had increased abundance of neutrophils and activated CD4 + T cells before treatment [68]. Similarly, specific signalling pathways, namely NFκB, TGF-β or JAK-STAT, were enriched at baseline in non-responders IFX-or VDZtreated patients [69,70]. Altogether, these studies highlight the enormous potential and versatility of transcriptomic data for biomarker identification.…”

Psychological impairment in inflammatory bowel diseases: the key role of coping and defense mechanisms

“…It is widely recognized UC mainly affects colon and rectum, while CD Crohn’s disease may involve the entire intestine, from mouth to anus (Bouwman et al ., 2022 ; Li et al ., 2022). It is often difficult to formulate a differential diagnosis, remaining this goal crucial for the appropriate treatment and management of these two pathologies (Bouwman et al ., 2022 ). IBDs inspired high quality research from all the world to deeply understand their underlying etiopathogenesis, course and outcome of such diseases.…”